How to Manage Patients with Lenalidomide-Refractory Multiple Myeloma

SIMPLE SUMMARY: Lenalidomide is considered a key drug in the treatment of patients with multiple myeloma (MM), an incurable haematological cancer. In fact, most of the regimens used to treat early stage MM patients contain lenalidomide. This extensive use, however, has now led to treatment resistance. In this review, we explore the different options available to these patients, summarise the current knowledge and explore potential future treatments. ABSTRACT: Although lenalidomide-based combinations, such as lenalidomide plus a proteasome inhibitor or an anti-CD38 monoclonal antibody, improve the overall response rate, progression-free survival, and overall survival of patients with relapsed/refractory multiple myeloma (RRMM), there is a tendency to use these regimens as a frontline treatment. This strategy has led to the development of refractoriness early in the disease course, usually after the patient’s first treatment. Since lenalidomide-free regimens have so far shown limited efficacy in lenalidomide-refractory patients, there is an unmet need for other treatment options. In this review, we discuss the therapeutic options available to treat the general population of lenalidomide-refractory patients (mono, double and triple refractory) and the subpopulation of patients with other high-risk features such as renal failure, extramedullary disease, and high-risk cytogenetics. Moreover, new promising individual therapies and the possible impact of immunotherapy in RRMM patients are debated.